rs76114496

chr15-63669656-T-Cchr15-63669656-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003922.4(HERC1):c.8088A>G(p.Thr2696=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00871 in 1,613,902 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0090 (87 hom.)
• Consequence: HERC1 NM_003922.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0260

Genes affected

HERC1 (HGNC:4867): (HECT and RLD domain containing E3 ubiquitin protein ligase family member 1) This gen encodes a member of the HERC protein family. This protein stimulates guanine nucleotide exchange on ARF1 and Rab proteins. This protein may be involved in membrane transport processes. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 15-63669656-T-C is Benign according to our data. Variant chr15-63669656-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 435412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.026 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00608 (926/152350) while in subpopulation NFE AF= 0.0105 (711/68036). AF 95% confidence interval is 0.00981. There are 7 homozygotes in gnomad4. There are 440 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HERC1	NM_003922.4	c.8088A>G	p.Thr2696=	synonymous_variant	40/78	ENST00000443617.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HERC1	ENST00000443617.7	c.8088A>G	p.Thr2696=	synonymous_variant	40/78	1	NM_003922.4	P1

Frequencies

GnomAD3 genomes AF: 0.00608 AC: 926 AN: 152232 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00720

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0104

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00519 AC: 1293 AN: 249094 Hom.: 9 AF XY: 0.00499 AC XY: 675 AN XY: 135146

Gnomad AFR exome AF: 0.00181

Gnomad AMR exome AF: 0.00264

Gnomad ASJ exome AF: 0.00318

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00144

Gnomad NFE exome AF: 0.00959

Gnomad OTH exome AF: 0.00430

GnomAD4 exome AF: 0.00899 AC: 13135 AN: 1461552 Hom.: 87 Cov.: 31 AF XY: 0.00870 AC XY: 6328 AN XY: 727076

Gnomad4 AFR exome AF: 0.00119

Gnomad4 AMR exome AF: 0.00271

Gnomad4 ASJ exome AF: 0.00398

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00176

Gnomad4 NFE exome AF: 0.0111

Gnomad4 OTH exome AF: 0.00684

GnomAD4 genome AF: 0.00608 AC: 926 AN: 152350 Hom.: 7 Cov.: 32 AF XY: 0.00591 AC XY: 440 AN XY: 74504

Gnomad4 AFR AF: 0.00171

Gnomad4 AMR AF: 0.00719

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.0105

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00771 Hom.: 5

Bravo AF: 0.00597

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	HERC1: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 06, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	6.6
Dann	Benign	0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs76114496; hg19: chr15-63961855; COSMIC: COSV71247845;